Optimal place of treatment for young infants aged less than 2 months with any one low-mortality-risk sign of possible serious bacterial infection
| ISRCTN | ISRCTN44033252 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN44033252 |
| Secondary identifying numbers | U1111-1251-1576 |
- Submission date
- 24/11/2020
- Registration date
- 20/01/2021
- Last edited
- 05/06/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Plain English summary of protocol
Background and study aims
Young infants up to 2 months old with clinically suspected sepsis are classified by the WHO algorithm as having Possible Serious Bacterial Infection (PSBI). WHO guidelines recommend that young infants with PSBI should be managed in a hospital with injectable antibiotics and supportive care. When referral to a hospital is not feasible, the guidelines recommend further classification of these young infants into those who are critically ill and those who have clinical severe infection (CSI). If a hospital referral is not feasible, infants with CSI can be managed on an outpatient basis with injectable gentamicin for 2 or 7 days and oral amoxicillin for 7 days. Previous research on the above guidelines has demonstrated that outpatient treatment is safe and effective when hospitalization is not feasible.
Overall a quarter to half of newborns in different settings are taken to a hospital. However, hospitalization has associated risks, so only those young infants with signs of PSBI who have a favourable benefit-risk ratio should be hospitalized.
Previous observational studies have shown that the fatality rate for young infants with clinical severe infection (CSI) treated at the hospital was higher compared to those treated on an outpatient basis. This could be due to: the infants who were taken to the hospital being sicker than those who were not, despite presentation with the same clinical signs; unstandardized or delayed treatment in hospitals and infants who were not taken to a hospital receiving standardized treatment immediately; or hospitalized infants might have suffered from an infection that was acquired in the hospital from a treatment-resistant pathogen which therefore has worse outcomes.
In contrast, the mortality rate was lower among those with any sign of critical illness who received in-hospital treatment, compared to those who received outpatient treatment. This seems logical because critically ill young infants need supportive care in addition to antibiotics, whereas infants with CSI primarily need antibiotic treatment.
This study will compare the outcomes of the treatment of infants with low-mortality-risk symptoms of a possible severe bacterial infection in either hospital or outpatient treatment settings. The overall aim is to generate knowledge that will allow for only young infants with PSBI who need inpatient treatment to be admitted to hospital and to treat others on an outpatient basis.
Who can participate?
Infants will be eligible if they are aged less than 2 months old and present at one of the participating hospitals with only one of the following three symptoms that suggest a low mortality risk of CSI: body temperature ≥38°C; severe chest indrawing; or fast breathing (in those aged <7 days old).
What does the study involve?
7000 eligible young infants will be randomly allocated to receive one of the following antibiotic treatments:
1. Injectable gentamicin (once daily) at the hospital for 2 days, and oral amoxicillin (twice daily) at home for 7 days
2. The WHO recommended antibiotic treatment with injectable ampicillin (twice daily), injectable gentamicin (once daily), and other supportive care, at the hospital for at least 7 days
The outcomes of these treatments will be compared by an independent assessor who will visit all enrolled young infants at 2, 4, 8, and 15 days after enrolment in the study.
What are the possible benefits and risks of participating?
Your infant will get treatment in hospital or as outpatient. There may not be a direct benefit for your infant and the society at this stage, but his/her participation will bring benefit for future generations. If the finding of this study shows benefits of Treatment B (outpatient treatment), you will have contributed to change global recommendation on care for young infants with a mild sign of infection. If the finding of this study shows benefits of Treatment A (standard hospital treatment), it will be recommended for all other young infants presenting with a mild sign of infection in your community.
Although the medicines being used in this study are used in young infants throughout the world and are generally known to be safe, they can rarely cause diarrhea, stomach ache or a skin rash. Since medicine is given in the home, there is a risk that response to medical problems will be slower there than in a hospital. Infants are monitored more closely in the hospital. This risk will be lowered if you contact the treating physician/nurse immediately if you see your infant has skin rash, diarrhea, or breathing problems. There is a very low risk of a serious allergic reaction. There is a very low risk of hearing problems or kidney damage. These reactions are almost never life-threatening. If the treating physician/nurse thinks it is necessary, we will treat these side effects by stopping the medicine earlier than planned. If this occurs, a different type of medicine will be used instead. Contact the study health worker or the person listed below if you have any questions about the drugs.
Where is the study run from?
The WHO is coordinating this study. While in each country, implementing partners are responsible for running the study. There will be seven study sites (four in Asia and three in Africa). In Asia, research teams from Bangladesh, India (two sites), and Pakistan will implement these studies, while in Africa, research teams from Ethiopia, Nigeria, and Tanzania will conduct this study.
When is the study starting and how long is it expected to run for?
From January 2021 to May 2024
Who is funding the study?
The Bill and Melinda Gates Foundation (BMGF) (USA)
Who is the main contact?
Dr Yasir Bin Nisar
nisary@who.int
Contact information
Public
Department of Maternal, Newborn, Child and Adolescent Health and Ageing
World Health Organization
Geneva
1211
Switzerland
 ORCID ID |
0000-0002-9720-5699 |
|---|---|
| Phone | +41 227915595 |
| nisary@who.int |
Scientific
Department of Maternal, Newborn, Child and Adolescent Health and Ageing
World Health Organization
Geneva
1211
Switzerland
| Phone | +41 227915595 |
|---|---|
| nisary@who.int |
Study information
| Study design | International multi-center interventional open-label two-arm individually-randomized controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| Scientific title | Optimizing place of treatment for young infants presenting with any low-mortality-risk sign of possible serious bacterial infection. |
| Study acronym | WHO PSBI |
| Study objectives | Young infants with only one low-mortality-risk sign of possible serious bacterial infection (PSBI) presenting to outpatient/emergency department of a hospital, who receive outpatient treatment, will experience a better, or at least non-inferior, clinical outcome than young infants that receive inpatient treatment. |
| Ethics approval(s) | 10/06/2020, WHO Research Ethics Review Committee (20, Avenue Appia, CH-1211 Geneva 27, Switzerland; +41 227912111; ercsec@who.int), ref: ERC.0003289 |
| Health condition(s) or problem(s) studied | Treatment of low-mortality-risk signs of possible serious bacterial infection in young infants |
| Intervention | Eligible participants will be randomised (1:1) to either intervention or control groups. A WHO statistician not otherwise associated with study implementation will generate a randomization scheme with random permuted bocks of variable size using a computer programme for both studies. The random allocation will be concealed in serially numbered, opaque, sealed envelopes. After obtaining consent, the research assistant will open the envelope with the next serial number, assign the young infant to one of the study groups, and record the assigned group in the case report form. The intervention group will receive an intramuscular injection of gentamicin for 2 days, and oral amoxicillin for 7 days on an outpatient basis. The dose of gentamicin (for strength 40 mg/ml) will be: 0.2 ml for 1.5 to 2.4 kg body weight, 0.4 ml for 2.5 to 3.9 kg body weight, or 0.6 ml for 4.0 to 5.9 kg body weight, once daily. The dose of amoxicillin (dispersible tablet 250 mg) will be 1/2 tablet for 1.5 to 3.9 kg body weight, or1 tablet for 4.0 to 5.9 kg body weight, twice daily. The control group will receive the WHO recommended antibiotic treatment with injectable ampicillin (twice daily), injectable gentamicin (once daily), and other supportive care, at the hospital for at least 7 days. |
| Intervention type | Mixed |
| Primary outcome measure | 1. Poor clinical outcome defined as any one of the following: 1.1. Death any time between baseline and 15 days 1.2. Presence of any sign of critical illness (no movement at all, unable to feed at all, or convulsions) or any sign suggestive of another serious infection (such as meningitis, or bone and joint infection) at 2, 4, and 8 days 1.3. Presence of any new sign of clinical severe infection (CSI) at 4 and 8 days 1.4. Persistence of the presenting sign at 8 days |
| Secondary outcome measures | There are no secondary outcome measures |
| Overall study start date | 01/01/2020 |
| Completion date | 15/05/2024 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Neonate |
| Upper age limit | 2 Months |
| Sex | Both |
| Target number of participants | 7000 |
| Total final enrolment | 7002 |
| Key inclusion criteria | 1. Aged <2 months 2. Living in a geographic area where follow-up for 14 days can be accomplished 3. Presenting to outpatient clinics or emergency rooms of participating hospitals with only one of the following low-risk signs of PSBI: 3.1. Body temperature ≥38°C 3.2. Severe chest indrawing 3.3. Fast breathing if aged <7 days |
| Key exclusion criteria | 1. Weight for age <-3 z, or weight <2 kg at the time of presentation if age at screening is less than 10 days 2. Signs of critical illness (no movement at all, unable to feed at all, or convulsions) 3. Signs of clinical severe infection (CSI) associated with a moderate risk of mortality (stopped feeding well, movement only on stimulation, low body temperature <35.5°C, or two or more of the six signs of CSI) 4. Any sign suggestive of another serious illness/condition, such as but not limited to: major congenital malformations, severe jaundice, conditions requiring major surgery, meningitis, bone or joint infection, or severe dehydration 5. Appearance of low-mortality risk signs in the first 24 h of life 6. Hospitalized for any illness in the previous 2 weeks 7. Prior use of injectable antibiotics for the same illness 8. Previously included in this study or currently included in any other study |
| Date of first enrolment | 24/06/2021 |
| Date of final enrolment | 30/04/2024 |
Locations
Countries of recruitment
- Bangladesh
- Ethiopia
- India
- Nigeria
- Pakistan
- Switzerland
- Tanzania
- United States of America
Study participating centres
House 37
Road 27
Block A
Dhaka
1213
Bangladesh
Addis Ababa
1000
Ethiopia
New Delhi
110016
India
Block I
Gokhale Vihar
Butler Colony
Lucknow
226001
India
Zaria
1044
Nigeria
National Stadium Rd
Karachi
74800
Pakistan
65001
Tanzania
Baltimore
21205
United States of America
Boston
02115
United States of America
1211
Switzerland
Sponsor information
Other
Department of Maternal, Newborn, Child and Adolescent Health and Ageing
Geneva
1211
Switzerland
| Phone | +41227915595 |
|---|---|
| nisary@who.int | |
| Website | http://www.who.int/maternal_child_adolescent/en/ |
"ROR" |
https://ror.org/01f80g185 |
Funders
Funder type
Charity
Government organisation / Trusts, charities, foundations (both public and private)
- Alternative name(s)
- Bill & Melinda Gates Foundation, Gates Foundation, BMGF, B&MGF, GF
- Location
- United States of America
Results and Publications
| Intention to publish date | 31/12/2024 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Other |
| Publication and dissemination plan | Planned publication in a high impact peer-reviewed journal. Dissemination of key findings with stakeholders will be conducted in each country after the completion of the study. |
| IPD sharing plan | The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | 14/07/2023 | 17/07/2023 | Yes | No |
Editorial Notes
05/06/2024: The following changes were made:
1. The overall study end date was changed from 31/12/2024 to 15/05/2024.
2. The recruitment end date was changed from 01/06/2024 to 30/04/2024.
3. The total final enrolment was added.
17/08/2023: The following changes were made to the study record:
1. The recruitment end date was changed from 01/08/2023 to 01/06/2024.
2. The overall study end date was changed from 31/12/2023 to 31/12/2024.
3. The intention to publish date was changed from 31/12/2023 to 31/12/2024.
17/07/2023: Publication reference added.
25/06/2021: The recruitment start date has been changed from 15/06/2021 to 24/06/2021.
03/06/2021: The recruitment start date has been changed from 01/06/2021 to 15/06/2021.
06/05/2021: The recruitment start date was changed from 01/05/2021 to 01/06/2021.
07/04/2021: The recruitment start date was changed from 15/01/2021 to 01/05/2021.
26/11/2020: Trial’s existence confirmed by the WHO Research Ethics Review Committee.
